Phase I study of domatinostat (4SC‐202), a class I histone deacetylase inhibitor in patients with advanced hematological malignancies

Abstract

Objectives Domatinostat (4SC‐202) is a selective class I histone deacetylase inhibitor (HDACi). This phase I study investigated safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and antitumor activity in patients with advanced hematological malignancies. Methods Domatinostat was administered orally once (QD) or twice daily (BID) on days 1‐14 with 7 days off or continuously days 1‐21 in a 3 + 3 design at 7 dose levels from 25 to 400 mg total daily dose (TDD). Twenty‐four patients were treated with domatinostat. Results No formal maximum tolerated dose (MTD) was determined. One dose‐limiting toxicity (DLT, grade 4 hypercalcemia) occurred during 200 mg BID continuous treatment. Six patients were reported with ≥ grade 3 treatment‐related adverse events (TRAE; grade 3 hematological in three patients, grade 3 and grade 4 liver enzyme increase in 2 patients, grade 4 pulmonary embolism, and grade 4 hypercalcemia in one patient each). Higher grade hepatic TRAE occurred in the 200 mg BID continuous treatment cohort. Out of 24 patients, 1 achieved a complete response, 1 achieved a partial response, and 18 had stable disease as best response. Conclusion Administration of domatinostat was safe, well tolerated with signs of antitumor activity. Four hundred milligram TDD in a 200 mg BID schedule (14 + 7) is the recommended phase II dose for monotherapy.

The HDAC Inhibitor Domatinostat Promotes Cell-Cycle Arrest, Induces Apoptosis, and Increases Immunogenicity of Merkel Cell Carcinoma Cells

“…Domatinostat is highly specific for HDAC 1-3 with inhibitory constant (Ki) values in the nM range. It is also an inhibitor for the histone demethylase LSD1, which is demonstrated to be a regulator of a wide spectrum of biological processes, involved in cancer development and progression (von Tresckow et al, 2019). Concomitant targeting of HDAC and LSD1 proved to be a promising strategy for the cancer treatment as it induces apoptosis by shifting the J o u r n a l P r e -p r o o f balance of anti-and pro-apoptotic BCL-2 family proteins (Haydn et al, 2017).…”

“…Concomitant targeting of HDAC and LSD1 proved to be a promising strategy for the cancer treatment as it induces apoptosis by shifting the J o u r n a l P r e -p r o o f balance of anti-and pro-apoptotic BCL-2 family proteins (Haydn et al, 2017). However, the dual inhibitory activity of domatinostat has not been scrutinized yet and requires additional experiments (von Tresckow et al, 2019).…”

“…Hence, we scrutinized the effects of domatinostat (aka 4SC-202), an orally available small molecule inhibitor selectively targeting class I HDACs (HDAC 1, 2 and 3), since it is currently be tested in the treatment of advanced MCC patients in combination with the anti-PD-L1 antibody avelumab (NCT04393753) 1 . Domatinostat also inhibits the lysine-specific histone demethylase 1A (LSD1) and the repressor element 1 (RE1)-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) at low µM concentrations (von Tresckow et al, 2019;Inui et al, 2017). Notably, dysregulation REST expression had been associated with the neuroendocrine differentiation of MCC cells (Chteinberg et al, 2018).…”

Domatinostat favors the immunotherapy response by modulating the tumor immune microenvironment (TIME)

“…Signs of anticancer activity were observed, including one patient with a complete response, one patient with a partial response and 18 patients with disease stabilization as the best overall response. Domatinostat was well tolerated, showing an acceptable safety profile [22].…”

Metformin and 4SC‐202 synergistically promote intrinsic cell apoptosis by accelerating ΔNp63 ubiquitination and degradation in oral squamous cell carcinoma

“…4SC‐202 is a novel selective class I histone deacetylase inhibitor. In vitro, 4SC‐202 was found to inhibit survival and proliferation of several type of cancer cells including hepatocellular carcinoma cell, colorectal cancer cell, medulloblastoma cell, and urothelial carcinoma cell; and phase I clinical trials for the treatment of hematological malignant tumor revealed that 4SC‐202 is safe, well tolerated with signs of antitumor activity . Thus, 4SC‐202 seems to be a promising treatment strategy for oral cancer.…”